Structure of 576-83-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Zhou, Tongliang ; Gao, Pengcheng ; Bisz, Elwira ; Dziuk, Błażej ; Lalancette, Roger ; Szostak, Roman , et al.
Abstract: We describe the development of [(NHC)Pd(cinnamyl)Cl] complexes of ImPy (ImPy = imidazo[1,5-a]pyridin-3-ylidene) as a versatile class of precatalysts for cross-coupling reactions. These precatalysts feature fast activation to monoligated Pd(0) with 1:1 Pd to ligand ratio in a rigid imidazo[1,5-a]pyridin-3-ylidene template. Steric matching of the C5-substituent and N2-wingtip in the catalytic pocket of the catalyst framework led to the discovery of ImPyMesDipp as a highly reactive imidazo[1,5-a]pyridin-3-ylidene ligand for Pd-catalyzed cross-coupling of nitroarenes by challenging C–NO2 activation. Kinetic studies demonstrate fast activation and high reactivity of this class of well-defined ImPy–Pd catalysts. Structural studies provide full characteristics of this new class of imidazo[1,5-a]pyridin-3-ylidene ligands. Computational studies establish electronic properties of sterically-restricted imidazo[1,5-a]pyridin-3-ylidene ligands. Finally, a scalable synthesis of C5-substituted imidazo[1,5-a]pyridin-3-ylidene ligands through Ni-catalyzed Kumada cross-coupling is disclosed. The method obviates chromatographic purification at any of the steps, resulting in a facile and modular access to ImPy ligands. We anticipate that well-defined [Pd–ImPy] complexes will find broad utility in organic synthesis and catalysis for activation of unreactive bonds.
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CAS No. : | 576-83-0 |
Formula : | C9H11Br |
M.W : | 199.09 |
SMILES Code : | CC1=C(Br)C(C)=CC(C)=C1 |
MDL No. : | MFCD00000073 |
InChI Key : | RRTLQRYOJOSPEA-UHFFFAOYSA-N |
Pubchem ID : | 68473 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.04 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.63 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.71 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.37 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.86 |
Solubility | 0.0278 mg/ml ; 0.000139 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.4 |
Solubility | 0.0791 mg/ml ; 0.000397 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.42 |
Solubility | 0.00766 mg/ml ; 0.0000385 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.88 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.15 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of bis(4-bromophenyl)(mesityl)borane To a stirred solution of 2-bromo-1,3,5-trimethylbenzene (5.9 g, 30.0 mmol) in dry Et2O (100 mL) is added dropwise n-butyllithium (1.60 M in hexane, 18.75 mL, 30.0 mmol) at -78 C. After stirring for 1 h, the mixture is added trimethyl borate (6.2 g, 60.0 mmol) and is stirred overnight at room temperature. The solvent of mixture is evaporated, and the residue is distilled under reduced pressure (200 torr) to afford clear liquid dimethyl mesitylboronate intermediate. To the solution of dimethyl mesitylboronate (1 g, 5.21 mmol) in dry THF (20 mL) is added (4-bromophenyl)magnesium bromide (0.5 M in THF, 32 mL, 16 mmol) at -78 C. under nitrogen atmosphere. The reaction mixture is allowed to stir at room temperature and poured into a large amount of water, and extracted with chloroform. The combined organic layer is washed with water, and dried over anhydrous Na2SO4. The residue is purified by column chromatography on silica gel (eluent: hexane/CHCl3=8:1, v/v) to afford a white solid (8.4 g, 63%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | TERT-BUTYLLITHIUM (90.6 mL, 154 mmol; 1.7 M in pentane) was added via cannula to a stirred solution of tetrahydrofuran (380 mL) under an atmosphere of nitrogen at room temperature. The reaction mixture was cooled to-78C before adding 2-bromomesitylene (11.3 mL, 74.1 mmol) dropwise. The reaction mixture was allowed to stir for 1 hour at- 78C. To the reaction mixture at-78C was added 4-methoxypyridine (5.79 ML, 57 mmol) dropwise, and the resulting mixture was stirred AT-23C for 3 hours. The reaction mixture was then re-cooled to-78C and DIMETHYLFORMAMIDE (6.62 mL, 85.5 mmol) was added and stirring was continued for 1 hour AT-78C. The reaction mixture was quenched slowly AT-78C with saturated aqueous sodium chloride solution (100 mL) and allowed to warm to room temperature slowly. To the reaction mixture was added diethyl ether (200 mL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150 mL) and the combined organic layers were dried over potassium carbonate (20 g). The potassium carbonate was removed by filtration and washed with diethyl ether (100 mL) and the solvent removed under reduced pressure. The resulting crude 4-methoxy-3- pyridinecarboxaldehyde was purified by column chromatography (SiO2, 5: 95 ethanol: ethyl acetate) to give 4.79 g of the title intermediate as a yellow solid (61% yield; >98% purity by'H NMR). Analytical Data : HNMR (300 MHz, CDCL) 8 10.43 (s, 1H, CHO), 8.87 (s, 1H, ArH), 8.63 (d, 1H, J= 6, ARH), 6.92 (d, 1H, J= 6, ART), 3.98 (s, 3H, CH30). |
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